组蛋白去乙酰化酶HDAC7在肺癌发生发展中的作用和机制

Lung cancer has the highest morbidity and mortality in China, fully the understanding the molecular mechanisms underlying lung cancer development is poor. Many evidences have demonstrated that epigenetic elements play important roes in cancer development, however one of major epigenetic modifiers, The function of histone deacetylase 7 (HDAC7) in cancers, especially in lung cancer, need to be further investigated. Our preliminary studies have revealed that the level of HDAC7 mRNA was negatively correlated with prognosis of lung cancer patients and reducing HDAC7 expression in K-Ras transgenic mice resulted in suppression of mouse lung tumorigenesis by promoting apoptosis and inhibiting cell proliferation. Our preliminary studies also showed that reducing HDAC7 expression in HDAC7+/-/K-Ras mice resulted in a dramatically increase of Stat3 activity in mouse lung tumors while overexpression of exogenous HDAC7 in human lung tumor cell line H1299 led to a decrease of Stat3 activity. Base on these results of preliminary studies, we hypothesize that HDAC7 gene promotes human lung tumorigenesis by inhibiting Stat3 activity. To test this hypothesis, we will study (1) the role of HDAC7 gene in human lung tumorigenesis using lung tumor samples collected from patients and human lung cancer cell lines; (2) the molecular mechanisms by which HDAC7 regulates lung cancer development using HDAC7+/-/K-Ras mice and human lung cancer cell lines as models. Our studies may provide valuable information for novel therapeutic strategy and personal therapy of lung cancers.

肺癌是中国发病率和死亡率最高的恶性肿瘤，但目前对肺癌发生发展的机制还缺乏全面了解。表观遗传修饰变异是癌症发生发展中的重要事件，而作为关键调节因子之一的组蛋白去乙酰化酶HDAC7在癌症特别是肺癌中的功能仍有待深入研究。我们前期研究结果显示： HDAC7 mRNA表达水平与病人预后负相关； 在K-Ras肺癌小鼠细胞降低HDAC7表达能促进细胞凋亡、抑制细胞增殖从而抑制肺癌发生发展；HDAC7低表达导致肺肿瘤中Stat3活性升高而HDAC7过表达则下调Stat3活性。我们假设：HDAC7抑制Stat3活性进而促进肺癌发生发展。我们计划(1)测定400例肺癌样品的HDAC7蛋白水平并分析其与肺癌病理分型和预后的关系，确定HDAC7在人肺癌中的作用；(2)以HDAC7+/-/K-Ras肺癌小鼠和人肺癌细胞株为模型阐明HDAC7调控肺癌发生发展的分子机制，为肺癌病人个性化诊断治疗的新策略提供理论依据。

肺癌是中国发病率和死亡率最高的恶性肿瘤，但目前对肺癌发生发展的机制还缺乏全面了解。表观遗传修饰变异是癌症发生发展中的重要事件，而作为关键调节因子之一的组蛋白去乙酰化酶HDAC7在癌症特别是肺癌中的功能仍有待深入研究。本研究结果显示：HDAC7表达水平与病人预后负相关，与对照K-Ras肺癌小鼠相比较，HDAC7+/-K-Ras小鼠肺肿瘤数量和负荷都大量减少，HDAC7低表达导致小鼠肺肿瘤中Stat3活性升高进而促进细胞增殖、抑制细胞凋亡、抑制肺癌发生发展。在人肺癌细胞株敲减HDAC7获得相似结果。本研究证明：显性负Stat3过表达能拯救HDAC7突变介导的小鼠肺肿瘤数量/负荷都减少的表型并促进人肺癌细胞肺癌增殖和凋亡。我们研究发现HDAC7和Stat3蛋白通过直接互作，促进Stat3的去乙酰化和降低酪氨酸磷酸化从而抑制Stat3活性。我们的研究还发现Stat3蛋白N端11个氨基酸组成了一个具有基本转录活性结构域。因此本研究确定HDAC7在人肺癌中的作用，初步阐明了HDAC7调控Stat3活性影响肺癌发生发展的分子机制，为肺癌病人个性化诊断治疗的新策略提供了理论依据。